PRODUCT MONOGRAPH. (zopiclone) Tablets, 5 mg and 7.5 mg. Hypnotic and Sedative

Transcription

1 PRODUCT MONOGRAPH Pr ACT ZOPICLONE (zopiclone) Tablets, 5 mg and 7.5 mg Hypnotic and Sedative Actavis Pharma Company 6733 Mississauga Road, Suite 400 Mississauga, Ontario L5N 6J5 Date of Revision: July 16, 2018 Control Number: ACT ZOPICLONE Page 1 of 40

2 Table of Contents PART I: HEALTH PROFESSIONAL INFORMATION... 3 SUMMARY PRODUCT INFORMATION... 3 INDICATIONS AND CLINICAL USE... 4 CONTRAINDICATIONS... 4 WARNINGS AND PRECAUTIONS... 5 ADVERSE REACTIONS DRUG INTERACTIONS DOSAGE AND ADMINISTRATION OVERDOSAGE ACTION AND CLINICAL PHARMACOLOGY STORAGE AND STABILITY SPECIAL HANDLING INSTRUCTIONS DOSAGE FORMS, COMPOSITION AND PACKAGING PART II: SCIENTIFIC INFORMATION PHARMACEUTICAL INFORMATION CLINICAL TRIALS DETAILED PHARMACOLOGY TOXICOLOGY REFERENCES PART III: CONSUMER INFORMATION ACT ZOPICLONE Page 2 of 40

3 PRODUCT MONOGRAPH Pr ACT ZOPICLONE (zopiclone) Tablets, 5 mg and 7.5 mg PART I: HEALTH PROFESSIONAL INFORMATION WARNING: RISKS FROM CONCOMITANT USE WITH OPIOIDS Concomitant use of zopiclone and opioids may result in profound sedation, respiratory depression, coma, and death (see WARNINGS, Risks from concomitant use of opioids and benzodiazepines or other CNS depressants). Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients for signs and symptoms of respiratory depression and sedation. SUMMARY PRODUCT INFORMATION Route of Administration Dosage Form / Strength Oral Tablet / 5 mg and 7.5 mg All Non medicinal Ingredients ACT ZOPICLONE 5 mg contains: Calcium Hydrogen Phosphate, HPMC 2910/Hypromellose 6cP, Lactose Monohydrate, Macrogol/PEG 3000, Magnesium Stearate, Potato Starch Dried, Silicon Dioxide, Sodium Starch Glycolate, Titanium dioxide, and Triacetine/Glycerol triacetate. ACT ZOPICLONE 7.5 mg contains: Calcium Hydrogen Phosphate, FD&C Blue #1/ Brilliant blue FCF Aluminum Lake, Macrogol/PEG 3350, Magnesium stearate, Polyvinyl alcohol (Partially hydrolyzed), Potato Starch Dried, Silicon Dioxide, Sodium Starch Glycolate, Talc and Titanium dioxide. ACT ZOPICLONE Page 3 of 40

4 INDICATIONS AND CLINICAL USE Sleep disturbance may be the presenting manifestation of a physical and/or psychiatric disorder. Consequently, a decision to initiate symptomatic treatment of insomnia should only be made after the patient has been carefully evaluated. Adults: ACT ZOPICLONE (zopiclone) is indicated for the short-term treatment and symptomatic relief of insomnia characterized by difficulty in falling asleep, frequent nocturnal awakenings and/or early morning awakenings. Treatment with zopiclone should usually not exceed 7-10 consecutive days. Use for more than 2-3 consecutive weeks requires complete re-evaluation of the patient. Prescriptions for zopiclone should be written for short-term use (7-10 days) and it should not be prescribed in quantities exceeding a 1-month supply. The use of hypnotics should be restricted for insomnia where disturbed sleep results in impaired daytime functioning. Geriatrics ( 65 years of age): Because some of the adverse effects of zopiclone may be dose related, the smallest possible effective dose should be described, especially for elderly patients. Inappropriate, heavy sedation in the elderly, may result in accidental events/falls (See DOSAGE AND ADMINISTRATION). Pediatrics (< 18 years of age): The safety and effectiveness of zopiclone in children and young adults below the age of 18 have not been established. Zopiclone is not indicated for pediatric patients. CONTRAINDICATIONS ACT ZOPICLONE is contraindicated in patients with: known hypersensitivity to the drug or to any component in its formulation. For a complete listing, of components, see DOSAGE FORMS, COMPOSITION AND PACKAGING. myasthenia gravis severe hepatic insufficiency severe impairment of respiratory function (e.g., significant sleep apnea syndrome). ACT ZOPICLONE Page 4 of 40

5 WARNINGS AND PRECAUTIONS WARNING: RISKS FROM CONCOMITANT USE WITH OPIOIDS Concomitant use of zopiclone and opioids may result in profound sedation, respiratory depression, coma, and death (see WARNINGS, Risks from concomitant use of opioids and benzodiazepines or other CNS depressants). Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients for signs and symptoms of respiratory depression and sedation. General Benzodiazepine and benzodiazepine-like compounds should be used with extreme caution in patients with a history of substance or alcohol abuse. Because some of the adverse effects of zopiclone may be dose related, the smallest possible effective dose should be prescribed for elderly patients. Inappropriate, heavy sedation in the elderly, may result in accidental events/falls. The use of the lowest effective dose is also consistent with management of other dose-related risks associated with zopiclone (see below: Amnesia, Complex sleep-related behaviours, CNS Depressant Effects and Next-Day Impairment, Drug Abuse, dependence/tolerance and withdrawal). The cause of insomnia should be identified whenever possible and the underlying factors treated before a hypnotic is prescribed. The failure of insomnia to remit after 7-10 days of treatment may indicate the presence of a primary psychiatric and/or medical illness or the presence of sleep state misperception. Worsening of insomnia or the emergence of new abnormalities of thinking or behaviour may be the consequence of an unrecognized psychiatric or physical disorder. These have also been reported to occur in association with the use of drugs that act at the benzodiazepine receptors. ACT ZOPICLONE should be used with caution in patients who in the past manifested paradoxical reactions to alcohol and/or sedative medications. Lactose is a non-medicinal ingredient in ACT ZOPICLONE 5 mg. Patients with rare hereditary diseases of galactose intolerance (galactosemia or glucose-galactose malabsorption) should not take ACT ZOPICLONE 5 mg. ACT ZOPICLONE 7.5 mg does not contain lactose. Drug Abuse, dependence/tolerance and withdrawal Use of sedative/hypnotics agents like ACT ZOPICLONE may lead to the development of ACT ZOPICLONE Page 5 of 40

6 physical and psychological dependence or abuse. The risk of dependence or abuse is increased with the dose and duration of treatment, if used with alcohol or other psychotropics, in patients with a history of alcoholism and/or drug abuse or in patients with marked personality disorders. Interdose daytime anxiety and rebound anxiety may increase the risk of dependency in zopiclone-treated patients. Once physical dependence has developed, abrupt termination of treatment will be accompanied by withdrawal symptoms. Withdrawal symptoms, similar in character to those noted with barbituates and alcohol (convulsions, tremor, abdominal and muscle cramps, vomiting, sweating, dysphoria, perceptual disturbances and insomnia) have occurred following abrupt discontinuation of benzodiazepines and benzodiazepine-like agents, including zopiclone. The more severe symptoms are usually associated with higher dosages and longer usage, although patients given therapeutic dosages for as few as 1-2 weeks can also have withdrawal symptoms including daytime anxiety between nightly doses. Consequently, abrupt discontinuation should be avoided and a gradual dosage tapering schedule is recommended in any patient taking the drug for more than a few weeks. The recommendation for tapering is particularly important in patients with a history of seizures (see ADVERSE REACTIONS, Withdrawal Symptoms). As with all hypnotics, repeat prescriptions should be limited to those who are under medical supervision. It may be useful to inform the patient when treatment is started that it will be of limited duration and to explain precisely how the dosage will be progressively decreased. Some loss of efficacy of other hypnotics may develop after repeated use. However, there was an absence of tolerance with zopiclone for treatment periods of up to 4 weeks. Hepatic/Biliary/Pancreatic/Renal Zopiclone should be given with caution to patients with impaired hepatic or renal function. Dosage adjustments are recommended (see DOSAGE AND ADMINISTRATION). Zopiclone is contraindicated in patients with severe hepatic insufficiency (see CONTRAINDICATIONS). Immune Severe Anaphylatic and Anaphylactoid Reactions: Rare cases of angioedema involving the tongue, glottis or larynx have been reported in patients after taking the first or subsequent doses of sedative-hypnotics, including zopiclone. Some patients have had additional symptoms such as dyspnea, throat closing or nausea and vomiting that suggest anaphylaxis. Some patients have required medical therapy in the emergency ACT ZOPICLONE Page 6 of 40

7 department. If angioedema involves the throat, glottis or larynx, airway obstruction may occur and be fatal. Patients who develop angioedema after treatment with ACT ZOPICLONE should not be rechallenged with the drug. Musculoskeletal Zopiclone is contraindicated in patients with myasthenia gravis (see CONTRAINDICATIONS). Neurologic Amnesia Anterograde amnesia of varying severity has been reported following therapeutic doses of benzodiazepines or benzodiazepine-like agents. The event is rare with zopiclone. Anterograde amnesia may occur, especially when sleep is interrupted or when retiring to bed is delayed after the intake of the tablet. Anterograde amnesia is a dose-related phenomenon and elderly subjects may be at particular risk. Cases of transient global amnesia and traveler s amnesia have also been reported in association with benzodiazepines, the latter in individuals who have taken the drug, often in the middle of the night, to induce sleep while travelling. Transient global amnesia and traveler s amnesia are unpredictable and not necessarily dose-related phenomena. To reduce the possibility of anterograde amnesia, patients should ensure that they take the tablet strictly when retiring for the night. Patients should be warned not to take zopiclone under circumstances in which a full night s sleep and clearance of the drug from the body are not possible before they need again to resume full activity. Complex sleep-related behaviours: Complex sleep-related behaviours such as sleep-driving (i.e., driving while not fully awake after ingestion of a sedative-hypnotic, with amnesia for the event) have been reported in patients who have taken zopiclone. Other potentially dangerous behaviours have been reported in patients who got out of bed after taking a sedative-hypnotic and were not fully awake, including preparing and eating food, making phone calls, leaving the house, etc. As with sleep-driving, patients usually do not remember these events. Although complex sleep-related behaviours may occur with zopiclone alone at therapeutic doses, the use of alcohol and other CNS-depressants with zopiclone appears to increase the risk of such behaviours, as does the use of zopiclone at doses exceeding the maximum recommended dose. ACT ZOPICLONE is not to be taken with alcohol. Caution is needed with concomitant use of other CNS depressants drugs. Caution is recommended in patients with a personal or family history of sleepwalking. Although complex sleep-related behaviours have been reported in patients with or without history of ACT ZOPICLONE Page 7 of 40

8 sleepwalking, it is possible that some predisposed patients are at increased risk of experiencing these complex behaviours during treatment with zopiclone. The use of zopiclone in patients with other disorders known to affect sleep and induce frequent awakenings (e.g. sleep apnea, Periodic Limb Movement Disorder, Restless Legs Syndrome) is discouraged, as they may be also at increased risk of complex sleep-related behaviours. Treatment with zopiclone is limited to a short duration (see INDICATIONS, DOSAGE AND ADMINISTRATION). Patients should be instructed not to exceed the recommended dose. Caution should be exercised with concomitant use of potent CYP3A4 inhibitors (see DRUG INTERACTIONS). Due to the risk to the patient and the community, discontinuation of ACT ZOPICLONE should be strongly considered for patients who report any such complex sleep-related behaviours. Rebound insomnia A transient syndrome whereby the symptoms that led to treatment with a benzodiazepine or benzodiazepine-like agent recur in an enhanced form, may occur on withdrawal of hypnotic treatment. It may be accompanied by other reactions including mood changes, anxiety and restlessness. Since the risk of such phenomena is greater after abrupt discontinuation of zopiclone, especially after prolonged treatment, it is, therefore recommended to decrease the dosage gradually and to advise the patient accordingly (see ADVERSE REACTIONS). It is important that the patient should be aware of the possibility of rebound phenomena, thereby minimizing anxiety over such symptoms should they occur while the medicinal product is being discontinued. CNS Depressant Effects and Next-Day Impairment Like other sedative/hypnotic drugs, ACT ZOPICLONE has CNS-depressant effects. Due to the rapid onset of action, ACT ZOPICLONE should be ingested immediately prior to going to bed. Patients should be cautioned against engaging in hazardous occupations requiring complete mental alertness or motor coordination such as operating machinery or driving a motor vehicle after ingesting the drug. This includes potential impairment of the performance of such activities that may occur the day following ingestion of ACT ZOPICLONE. The risk of next day psychomotor impairment, including impaired driving, is increased if ACT ZOPICLONE is taken with less than a full night of sleep remaining; if a higher dose than the recommended dose is taken; if co-administered with other CNS depressants; or if co-administered with other drugs that increase the blood level of ACT ZOPICLONE Page 8 of 40

9 zopiclone. Patients should be cautioned against taking ACT ZOPICLONE in these circumstances. The lowest effective dose for the patient should be used. ACT ZOPICLONE is not to be taken with alcohol or other sedative hypnotics (including other zopiclone products) at bedtime or the middle of the night. If concomitant use of another CNS depressant or a drug that increases zopiclone blood levels is clinically warranted, dosage adjustments of ACT ZOPICLONE may be necessary. Even if ACT ZOPICLONE is taken as instructed, some patients may still have zopiclone blood levels in the morning high enough to produce impairment (see DOSAGE AND ADMINISTRATION and DRUG INTERACTIONS). Patient counseling information regarding next-day impairment: Tell patients that ACT ZOPICLONE has the potential to cause next-day impairment, and that this risk is increased if dosing instructions are not carefully followed. Tell patients not to drive a car or engage in hazardous activities requiring complete alertness until they experience how the drug affects them the next day. Tell patients that if they took ACT ZOPICLONE as instructed and do not feel drowsy in the morning, they still have to wait for at least 12 hours after dosing before driving or engaging in other activities requiring full mental alertness, especially for elderly patients and for patients who take the 7.5 mg dose. Inform patients that impairment can be present despite feeling fully awake. Risks from concomitant use of opioids and benzodiazepines and other CNS depressants: Concomitant use of benzodiazepines and other CNS depressants, including zopiclone, and opioids may result in profound sedation, respiratory depression, coma, and death. Because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioid analgesics alone. Because of similar pharmacological properties, it is reasonable to expect similar risk with the concomitant use of other CNS depressant drugs with opioid analgesics. If a decision is made to prescribe zopiclone concomitantly with opioids, prescribe the lowest effective dosages and minimum durations of concomitant use. In patients already receiving an opioid analgesic, prescribe a lower initial dose of zopiclone than indicated in the absence of an opioid, and titrate based on clinical response. If an opioid analgesic is initiated in a patient already taking zopiclone, prescribe a lower initial dose of the opioid analgesic, and titrate based on clinical response. Follow patients closely for signs and symptoms of respiratory depression and sedation (see DRUG INTERACTIONS). ACT ZOPICLONE Page 9 of 40

10 Advise both patients and caregivers about the risks of respiratory depression and sedation when zopiclone is used with opioids. Advise patients not to drive or operate heavy machinery until the effects of concomitant use of the opioid have been determined (see Serious Warning and Precautions box, and WARNINGS, CNS Depressant Effects and Next-Day Impairment). Psychiatric Abnormal thinking and behavioural changes: Abnormal thinking and other behavioural changes have been reported to occur in association with the use of benzodiazepines and benzodiazepine-like agents including zopiclone, although rarely (see ADVERSE REACTIONS). Some of the changes may be characterized by decreased inhibition, e.g., aggression or extroversion that seems excessive, similar to that seen with alcohol and other CNS depressants (e.g., sedative/hypnotics). Particular caution is warranted in patients with a history of violent behaviour and a history of unusual reactions to sedatives including alcohol and the benzodiazepines or benzodiazepine-like agents. Psychotic behavioural changes that have been reported include abnormal behaviour, restlessness, agitation, irritability, hallucinations, delusion, anger, nightmare and depersonalization. Abnormal behaviours associated with the use of benzodiazepines or benzodiazepine-like agents have been reported more with chronic use and/or high doses but they may occur during the acute, maintenance or withdrawal phases of treatment. It can rarely be determined with certainty whether a particular instance of abnormal behaviours listed above is drug induced, spontaneous in origin, or a result of an underlying psychiatric disorder. Nevertheless, the emergence of any new behavioural sign or symptom of concern requires careful and immediate evaluation. Should these occur, use of the product should be discontinued. These reactions are more likely to occur in the elderly. Cognitive Function: The benzodiazepines and benzodiazepine-like agents affect mental efficiency, e.g., concentration, attention and vigilance. The risk of confusion is greater in the elderly and in patients with cerebral impairment. Anxiety, restlessness: An increase in daytime anxiety and/or restlessness have been observed during treatment with zopiclone. This may be a manifestation of interdose withdrawal, due to the short elimination half-life of the drug. Depression and Suicidality: Caution should be exercised if zopiclone is prescribed to patients with signs and symptoms of depression that could be intensified by hypnotic drugs. The potential for self-harm (e.g., intentional overdose) is high in patients with depression and thus, the least amount of drug that is feasible should be available to them at any one time. ACT ZOPICLONE Page 10 of 40

11 As with other hypnotics, ACT ZOPICLONE does not constitute a treatment of depression and may even mask its symptoms. Several epidemiological studies show an increased incidence of suicide and suicide attempt in patients with or without depression, treated with benzodiazepines and other hypnotics, including zopiclone. A causal relationship has not been established. Respiratory Zopiclone should be given with caution to patients with chronic pulmonary insufficiency. Dosage adjustments are recommended (see DOSAGE AND ADMINISTRATION). Respiratory depression has been reported in patients with compromised respiratory function. As hypnotics have the capacity to depress respiratory drive, precautions should be observed if ACT ZOPICLONE is prescribed to patients with compromised respiratory function. ACT ZOPICLONE is contraindicated in those with severe impairment of respiratory function, e.g. significant sleep apnea syndrome (see CONTRAINDICATIONS). Special Populations Pregnant Women: The use of zopiclone during pregnancy is not recommended. If zopiclone is prescribed to a woman of child-bearing potential, the patient should be warned of the potential risk to a fetus and advised to consult her physician regarding the discontinuation of the drug if she intends to become pregnant or suspects that she is pregnant. Zopiclone crosses the placenta. Benzodiazepines may cause fetal damage when administered during pregnancy. During the first trimester of pregnancy, several studies have suggested an increased risk of congenital malformation associated with the use of benzodiazepines. In certain epidemiological case-control studies, an increased incidence of cleft lip and palate was observed with benzodiazepines. During the last weeks of pregnancy or during labour, ingestion of therapeutic doses of benzodiazepine hypnotic drugs has resulted in neonatal CNS depression due to transplacental distribution. Similar effects can be expected to occur with zopiclone, due to its pharmacological effects. Cases of reduced fetal movement and fetal heart rate variability have been described after administration of benzodiazepines during the second and/or third trimester of pregnancy. Administration of zopiclone during the late phase of pregnancy or during labour has been associated with effects on the neonate, such as hypothermia, hypotonia, feeding difficulties (which may result in poor weight gain) and respiratory depression. A child born to a mother who took sedative/hypnotics agents chronically during the latter stages of pregnancy may have developed physical dependence and may be at risk for developing ACT ZOPICLONE Page 11 of 40

12 withdrawal symptoms in the postnatal period. Appropriate monitoring of the newborn in the postnatal period is recommended. Nursing Women: Zopiclone is excreted in human milk, and its concentration may reach 50% of the plasma levels. Insufficient data are available on zopiclone to assess its safety during lactation. Therefore, the administration of zopiclone to nursing mothers is not recommended. Pediatrics (< 18 years of age): The safety and effectiveness of zopiclone in children and young adults below the age of 18 have not been established. ACT ZOPICLONE should not be prescribed in pediatric patients. Geriatrics ( 65 years of age): Elderly patients are especially susceptible to dose-related effects, such as drowsiness, dizziness, or impaired coordination. Inappropriate, heavy sedation may result in accidental events or falls. Therefore, the ACT ZOPICLONE dose in elderly patients should not exceed 5 mg (see DOSAGE AND ADMINISTRATION, Geriatric patients). Anterograde amnesia is a dose-related phenomenon and elderly subjects may be at particular risk. ADVERSE REACTIONS Adverse Drug Reaction Overview The most common adverse reaction seen with zopiclone is taste alteration (bitter taste). Severe drowsiness and/or impaired coordination are signs of drug intolerance or excessive doses. Clinical Trial Adverse Drug Reactions Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates. The following adverse events were observed in patients receiving zopiclone. In the absence of an established cause-effect relationship those adverse reactions that were observed more frequently with zopiclone than with a placebo are in italic. Cardiovascular: Central Nervous System: palpitations Somnolence, dizziness, confusion, anterograde amnesia or memory impairment, feeling of drunkenness, euphoria, nightmares, agitation, anxiety or nervousness, hostility, depression, decreased libido, libido disorder, coordination abnormality, headache, hypotonia, tremor, muscle spasms, paresthesia, and speech ACT ZOPICLONE Page 12 of 40

13 disorder. Hallucinations, aggression, irritability and fall (predominantly in elderly patients). Dermatologic: rash, spots on skin, sweating, pruritus. Rashes and pruritus may be a sign of drug hypersensitivity; discontinue if this occurs. Angioedema and/or anaphylactic reactions have been reported very rarely. Digestive: General Disorders and Administration Site Conditions: Metabolic and nutritional: Musculoskeletal: Respiratory: Special senses: bitter taste, dry mouth, coated tongue, bad breath, nausea, vomiting, diarrhea, constipation, anorexia or increased appetite. asthenia, chills, fatigue weight loss limb heaviness dyspnea amblyopia Geriatric patients: Geriatric patients tended to have a higher incidence of palpitations, vomiting, anorexia, sialorrhea, confusion, agitation, anxiety, tremor and sweating than younger patients. Anterograde amnesia is a dose-related phenomenon and elderly subjects may be at particular risk. Withdrawal symptoms: Withdrawal syndrome has been reported upon discontinuation of zopiclone (See WARNINGS AND PRECAUTIONS, Dependence/Tolerance). Withdrawal symptoms vary and may include rebound insomnia, muscle pain, anxiety, tremor, sweating, agitation, confusion, headache, palpitations, tachycardia, delirium, nightmares, irritability. In severe cases the following symptoms may occur: derealisation, depersonalisation, hyperacusis, numbness and tingling of the extremities, hypersensitivity to light, noise and physical contact, hallucinations. In very rare cases, seizures may occur. Abnormal Hematologic and Clinical Chemistry Findings There have been sporadic reports of abnormal laboratory test values. Mild to moderate increases in serum transaminase and/or blood alkaline phosphatase have been reported very rarely. ACT ZOPICLONE Page 13 of 40

14 Post-Market Adverse Drug Reactions Psychiatric disorders: restlessness, delusion, anger, abnormal behaviours (possibly associated with amnesia) and somnambulism (see WARNINGS, Complex sleep-related behaviours), withdrawal syndrome and dependence have been reported rarely. Respiratory Nervous system disorder: Eye disorder: Gastrointestinal disorders: respiratory depression ataxia, paresthesia (not associated with withdrawal), disturbance in attention diplopia dyspepsia Musculoskeletal and connective tissue disorders: muscular weakness. DRUG INTERACTIONS Overview The risk of drug interaction arising from displacement of bound drug is low. Drug-Drug Interactions CNS Depressants Zopiclone may produce additive CNS depressant effects when co-administered with sedative antihistamines, anticonvulsants, narcotic analgesics, anesthetics, or psychotropic medications such as antipsychotics (neuroleptics), hypnotics, anxiolytics/sedatives, and antidepressant agents which themselves can produce CNS depression. In the case of narcotic analgesics, enhancement of euphoria may also occur leading to an increase in psychological dependence. Drugs Affecting Cytochrome P450 Enzymes Since zopiclone is metabolized by the cytochrome P450 (CYP) 3A4 isoenzyme (see ACTION AND CLINICAL PHARMACOLOGY, Pharmacokinetics, Metabolism), plasma levels of zopiclone may be increased when co-administered with CYP3A4 inhibitors, such as erythromycin, clarithromycin, ketoconazole, itraconazole, and ritonavir. A dose reduction for ACT ZOPICLONE may be required when it is co-administered with CYP3A4 inhibitors. Conversely, plasma levels of zopiclone may be decreased when co-administered with CYP3A4 inducers, such as rifampicin or rifampin, carbamazepine, phenobarbital, phenytoin, and St. John s wort. A dose increase for ACT ZOPICLONE may be required when it is co-administered with CYP3A4 inducers. ACT ZOPICLONE Page 14 of 40

15 The effect of erythromycin on the pharmacokinetics of zopiclone has been studied in 10 healthy subjects. The AUC of zopiclone is increased by 80% in presence of erythromycin. The hypnotic effect of zopiclone may be enhanced when administered with erythromycin. Opioids Due to additive CNS depressant effect, the concomitant use of benzodiazepines or other CNS depressants, including zopiclone, and opioids increases the risk of profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations of concomitant use of benzodiazepines and opioids to the minimum required. Follow patients closely for respiratory depression and sedation (see Serious Warning and Precautions box, and WARNINGS AND PRECAUTIONS, Risks from concomitant use of opioids and benzodiazepines or other CNS depressants). Drug-Food Interactions No data is available. Drug-Herb Interactions No data is available. Drug-Lifestyle Interactions Concomitant intake with alcohol is not recommended (see WARNINGS AND PRECAUTIONS, Complex sleep-related behaviours). Zopiclone may produce additive CNS depressant effects when co-administered with alcohol. DOSAGE AND ADMINISTRATION Recommended Dose and Dosage Adjustment Use the lowest effective dose of ACT ZOPICLONE for the patient. Treatment with zopiclone should usually not exceed 7-10 consecutive days. Use for more than 2-3 consecutive weeks requires complete re-evaluation of the patient. Adult dose: The recommended initial dose is 3.75 mg (one-half of a 7.5 mg tablet). The dose can be increased to 5 mg and further to 7.5 mg if clinically indicated. In some patients, the higher doses result in zopiclone blood levels in the morning high enough to produce impairment of driving and other activities that require full alertness (see WARNINGS AND PRECAUTIONS, CNS Depressant Effects and Next-Day Impairment). The 7.5 mg dose should not be exceeded (see WARNINGS and PRECAUTIONS). ACT ZOPICLONE Page 15 of 40

16 Geriatric patients ( 65 years of age): In the elderly and/or debilitated patient an initial dose of 3.75 mg (one-half of a 7.5 mg tablet) at bedtime is recommended. The dose may be increased to a maximum of 5 mg if the starting dose does not offer adequate therapeutic effect. Patients with impaired liver function: The recommended dose is 3.75 mg (one-half of a 7.5 mg tablet) depending on acceptability and efficacy. If clinically indicated, a 5 mg may be used with caution in appropriate cases. ACT ZOPICLONE is contraindicated in patients with severe hepatic insufficiency (see CONTRAINDICATIONS). Patients with renal insufficiency: Although no accumulation of zopiclone or of its metabolites has been detected in cases of renal insufficiency, it is recommended that patients with impaired renal function should start treatment with 3.75 mg (one-half of a 7.5 mg tablet). If clinically indicated, a 5 mg may be used with caution in appropriate cases. Patients with chronic respiratory insufficiency: The recommended dose is 3.75 mg (one-half of a 7.5 mg tablet) depending on acceptability and efficacy. Up to 7.5 mg may be used with caution in appropriate cases. ACT ZOPICLONE is contraindicated in patients with severe impairment of respiratory function, e.g., significant sleep apnea syndrome (see CONTRAINDICATIONS). Use with potent CYP3A4 inhibitors: An initial dose of 3.75 mg (one-half of a 7.5 mg tablet) at bedtime is recommended (see DRUG INTERACTIONS). If clinically indicated, a 5 mg may be used with caution in appropriate cases. Use with CNS depressants: Dosage adjustment may be necessary when ACT ZOPICLONE is combined with other CNS-depressants because of the potentially additive effects (see DRUG INTERACTIONS). Pediatrics (< 18 years of age) ACT ZOPICLONE is not indicated for patients under 18 years of age. Administration The product should be taken just before retiring for the night. OVERDOSAGE For management of a suspected drug overdose, contact your regional Poison Control Centre immediately. ACT ZOPICLONE Page 16 of 40

17 Signs and Symptoms: Overdose is usually manifested by varying degrees of central nervous system depression ranging from drowsiness to coma according to the quantity ingested. In mild cases, symptoms include drowsiness, confusion, and lethargy; in more severe cases, symptoms may include ataxia, hypotonia, hypotension, methaemoglobinaemia, respiratory depression, and coma. Overdose should not be life threatening unless combined with other CNS depressants, including alcohol. Other risk factors, such as the presence of concomitant illness and the debilitated state of the patient, may contribute to the severity of symptoms and very rarely can result in fatal outcome. In voluntary or accidental cases of zopiclone overdosage involving doses up to 340 mg, the principal effects reported were prolonged sleep, drowsiness, lethargy and ataxia. Recommended Treatment: Symptomatic and supportive treatment in adequate clinical environment is recommended, attention should be paid to respiratory and cardiovascular functions. Gastric lavage or activated charcoal is only useful when performed soon after ingestion. Hemodialysis is of no value due to the large volume of distribution of zopiclone. Flumazenil may be a useful antidote; however, flumazenil administration may contribute to the appearance of neurological symptoms (agitation, anxiety, convulsions and emotional lability). Intravenous fluids should be administered as needed. Poison Control Center: As with the management of all overdosage, the possibility of multiple drug ingestion should be considered. The physician may wish to consider contacting a poison control center for up-todate information on the management of hypnotic drug product overdosage. ACTION AND CLINICAL PHARMACOLOGY Mechanism of Action Zopiclone, a cyclopyrrolone derivative, is a short-acting hypnotic agent. Zopiclone is structurally unrelated to existing hypnotics. However, the pharmacological profile of zopiclone is similar to that of the benzodiazepines. Zopiclone pharmacological properties are: hypnotic, sedative, anxiolytic, anti-convulsant, muscle-relaxant. These effects are related to a specific agonist action at central receptors belonging to the GABAa macromolecular complex, modulating the opening of the chloride ion channel. Pharmacodynamics In sleep laboratory studies of one to 21-day duration in man, zopiclone reduced sleep latency, increased the duration of sleep and decreased the number of nocturnal awakenings. Zopiclone delayed the onset of REM sleep but did not reduce consistently the total duration of REM ACT ZOPICLONE Page 17 of 40

18 periods. The duration of stage 1 sleep was shortened, and the time spent in stage 2 sleep increased. In most studies, stage 3 and 4 sleep tended to be increased, but no change and actual decreases have also been observed. The effect of zopiclone on stage 3 and 4 sleep differs from that of the benzodiazepines, which suppress slow wave sleep. The clinical significance of this finding is not known. With hypnotic drugs, the duration of hypnotic effect and the profile of unwanted effects may be influenced by the alpha (distribution) (t 1/2 α) and beta (elimination) (t 1/2 β) half-lives of the administered drug and any active metabolites formed. When half-lives are long, the drug or metabolite may accumulate during periods of nightly administration and be associated with impairments of cognitive and motor performance during waking hours. If half-lives are short, the drug and metabolites will be cleared before the next dose is ingested, and carry-over effects related to sedation or CNS depression should be minimal or absent. If the drug has a very short elimination half-life, it is possible that a relative deficiency (i.e., in relation to the receptor site) may occur at some point in the interval between each night s use. This sequence of events may account for two clinical findings reported to occur after several weeks of nightly use of rapidly eliminated benzodiazepines or benzodiazepine-like hypnotics: 1) increased wakefulness during the last third of the night and 2) the appearance of increased day-time anxiety (see WARNINGS AND PRECAUTIONS). During nightly use and for an extended period, pharmacodynamic tolerance or adaptation to some effects of benzodiazepines or benzodiazepine-like hypnotics may develop. However in two sleep laboratory studies involving 17 patients, there was an absence of tolerance with zopiclone for treatment periods of more than 4 weeks. Rebound insomnia: Some manifestations of rebound insomnia have been reported both in sleep laboratory and clinical studies following the withdrawal of zopiclone (see WARNINGS AND PRECAUTIONS). Zopiclone treatment was associated with dose-related residual effects (see WARNINGS AND PRECAUTIONS). Pharmacokinetics Absorption: Zopiclone is rapidly and well absorbed. Bioavailability is more than 75%, indicating the absence of a significant first-pass effect. After the administration of 3.75 and 7.5 mg doses, peak plasma concentrations of 30 and 60 ng/ml, respectively were reached in less than 2 hours. Absorption was similar in males and females. Repeated daily administration of a 7.5 mg oral dose for 14 days did not change the pharmacokinetic characteristics of zopiclone and did not lead to accumulation. Distribution: Zopiclone is rapidly distributed from the vascular compartment (distribution half- ACT ZOPICLONE Page 18 of 40

19 life [t 1/2 α]: 1.2 hours) while the elimination half-life is approximately 5 hours (range: 3.8 to 6.5 hours). Plasma protein binding is low (approximately 45% in the ng/ml concentration range) and non saturable. The risk of drug interaction arising from displacement of bound drug is low. The distribution volume is liters. Metabolism: Zopiclone is extensively metabolized by three major pathways; only about 4 to 5% of the drug is excreted unchanged in the urine. An in vitro study indicates that cytochrome P450 (CYP) 3A4 is the major isoenzyme involved in the metabolism of zopiclone to both metabolites, and that CYP2C8 is also involved with N- desmethyl zopiclone formation. The principal metabolites are the N-oxide derivative (~12%), which has a weak pharmacological activity in animals, and the N-desmethyl metabolite (~16%), which is pharmacologically inactive. Their apparent half-lives evaluated from the urinary data are approximately 4.5 and 7.4 hours, respectively. Both metabolites are excreted renally. Other metabolites resulting from oxidative decarboxylation are partly eliminated via the lung as carbon dioxide. In animals, zopiclone did not induce hepatic microsomal enzymes. Excretion: Excretion studies, using C 14 -zopiclone have shown that more than 90% of the administered dose was excreted over a period of 5 days, 75% being eliminated in the urine and 16% in the feces. The low renal clearance of unchanged zopiclone (mean 8.4 ml/min) compared with that of plasma (232 ml/min) indicates that zopiclone clearance is mainly metabolic. Special Populations and Conditions Pediatrics: No data is available. Geriatrics: In elderly subjects, the absolute bioavailability of zopiclone was increased (94% vs 77% in young subjects) and the elimination half-life prolonged (~7 hours). Accumulation has not been observed on repeated dosing. Patients with hepatic insufficiency: elimination half-life was substantially prolonged (11.9 hours) and time to peak plasma levels delayed (3.5 hours). Consequently, lower doses are recommended (see DOSAGE AND ADMINISTRATION). In cirrhotic patients, the plasma clearance of zopiclone is reduced by approximately 40% in relation with the decrease of the demethylation process. Therefore, dosage will have to be modified in these patients. ACT ZOPICLONE Page 19 of 40

20 Patients with mild to moderate renal insufficiency: the pharmacokinetics of zopiclone were not affected. In renal insufficiency, no accumulation of zopiclone or of its metabolites has been detected after prolonged administration. Zopiclone is removed by hemodialysis; however, hemodialysis is of no value in treating overdose due to the large volume of distribution of zopiclone (see also OVERDOSAGE). Hemodialysis did not appear to increase the plasma clearance of the drug. Lactating women: Zopiclone was present in the milk, its concentration paralleled plasma levels but was about 50% lower. (See WARNINGS AND PRECAUTIONS, Nursing women). STORAGE AND STABILITY Store at room temperature (15ºC - 30ºC). Protect from light and moisture. SPECIAL HANDLING INSTRUCTIONS Keep in a safe place out of reach of children. DOSAGE FORMS, COMPOSITION AND PACKAGING ACT ZOPICLONE (zopiclone) 5 mg is supplied as a white to off-white, round, coated, convex tablet, with Z5 on one side and on the other side. ACT ZOPICLONE (zopiclone) 7.5 mg is supplied as a blue, oval, coated, convex tablet with Z7.5 on one side and on the other side. Composition: ACT ZOPICLONE tablets 5 mg and 7.5 mg contain zopiclone as the medicinal ingredient. Zopiclone 5 mg also contains : Zopiclone 7.5 mg also contains : Non medicinal ingredients : Calcium Hydrogen Phosphate, HPMC 2910/Hypromellose 6cP, Lactose Monohydrate, Macrogol/PEG 3000, Magnesium Stearate, Potato Starch Dried, Silicon Dioxide, Sodium Starch Glycolate, Titanium dioxide, and Triacetine/Glycerol triacetate. Non medicinal ingredients : Calcium Hydrogen Phosphate, FD&C Blue #1/ Brilliant blue FCF Aluminum Lake, Macrogol/PEG 3350, Magnesium stearate, Polyvinyl alcohol (Partially hydrolyzed), Potato Starch Dried, Silicon Dioxide, Sodium Starch Glycolate, Talc and Titanium dioxide. Packaging: Available in HDPE bottles of 100 and 500 tablets. ACT ZOPICLONE Page 20 of 40

21 PART II: SCIENTIFIC INFORMATION PHARMACEUTICAL INFORMATION Drug Substance Proper name: Zopiclone Chemical name: 4-methyl-1-piperazinecarboxylic acid ester with 6-(5- chloro-2-pyridyl)-6,7-dihydro-7-hydroxy-5h-pyrrolo[3,4- b] pyrazin-5-one Molecular formula: C 17 H 17 ClN 6 O 3 Molecular mass: g/mol Structural formula: Physicochemical properties: White or slightly yellowish crystalline powder. It melts at about 177ºC with decomposition. Zopiclone is practically insoluble in water and in ethanol. Freely soluble in dichloromethane, soluble in isopropyl alcohol, chloroform, dimethylformamide, acetonitrile, and sparingly soluble in acetone. Dissolves in dilute mineral acids. ACT ZOPICLONE Page 21 of 40

22 CLINICAL TRIALS A single-dose, cross-over design comparative bioavailability study of ACT ZOPICLONE mg tablets and Imovane mg tablets has been performed in 26 healthy volunteers under fasted conditions. A summary of the bioavailability data is tabulated below. Summary Table of the Comparative Bioavailability Data + Zopiclone Fasted Study (1 x 7.5 mg) From measured data Geometric Mean Arithmetic Mean (CV %) Parameter AUC T (ng.h/ml) AUC ω (ng.h/ml) AUC RefTmax (ng.h/ml) C max (ng/ml) T max * (h) T ½ ** Test ACT ZOPICLONE Tablets 7.5 mg (19.8) (19.0) (89.7) (26.8) Reference Imovane Tablets 7.5 mg (20.0) (19.2) (71.3) (23.1) 0.84 ( ) 0.84 ( ) % Ratio of Geometric Means 90 % Confidence Interval (24.4) 4.63 (24.4) (h) + From measured and log transformed data, uncorrected for potency. The reference product Imovane 7.5 mg is manufactured by sanofi-aventis Canada Inc. and was purchased in Canada. * expressed as median (range) only. ** expressed as arithmetic mean (CV%) only. ACT ZOPICLONE Page 22 of 40

23 DETAILED PHARMACOLOGY Zopiclone, a cyclopyrrolone derivative, is a chemically novel hypnotic agent. However, the pharmacological and behavioural evaluation of the drug has shown that its effects are similar to those of the benzodiazepines. 1. CNS Activity Zopiclone antagonizes chemically and electroshock-induced seizures in mice and rats. While it potently affects convulsive conditions that involve GABA, it is relatively ineffective when glycine, another inhibitory amino acid, is involved. Zopiclone exerts muscle relaxant activity; it inhibits the traction grasping reflex in mice, reduces the ability of mice and rats to remain on a rotarod and inclined screen, respectively, relaxes the hind legs of normal cats and blocks polysynaptic reflexes in chloralosed cats. Zopiclone also exerts antiaggressive activity; it inhibits footshock-induced fighting behaviour in mice and septal lesion-induced aggression in rats. In a conflict situation, the drug increases punishment-suppressed lever-pressing behaviour, which is indicative of anxiolytic activity. Non-punished responding, indicative of non-specific sedation, is suppressed only at higher doses. While zopiclone does not cause loss of righting reflex in normal mice, it potentiates narcosis induced by hexobarbital or ethanol. In a drug discrimination paradigm, where rats are trained to discriminate drug from saline, the zopiclone discriminative stimulus generalized to several benzodiazepines as well as to pentobarbital. The finding that the benzodiazepines and a barbiturate were able to substitute for zopiclone indicates that zopiclone belongs to the same class of drugs. Tolerance does not develop to the behavioural effects of zopiclone, since the anticonvulsant and taming ED 50 s are similar in naïve and zopiclone-treated animals. 2. Receptor binding studies Zopiclone has a high and specific affinity for benzodiazepine binding sites in several rat brain regions. The drug can inhibit the binding of 3 H-benzodiazepines, but can itself label the sites that are recognized both by benzodiazepine agonists and Ro , a benzodiazepine antagonist. Zopiclone does not recognize the peripheral benzodiazepine receptor sites and lacks affinity for the serotonin, Gaba, α 1 and α 2 adrenergic, and dopamine receptors. The interaction of zopiclone with the benzodiazepine receptor/gaba receptor/chloride ACT ZOPICLONE Page 23 of 40

24 channel complex differs somewhat from that of the benzodiazepines; while it decreases cgmp concentration in rat cerebellum, its binding is not enhanced either by GABA or by the chloride anion. 3. Dependence Liability In barbital-dependent rhesus monkeys, zopiclone suppressed the abstinence symptoms which appeared upon withdrawal. Partial and complete suppression was observed at 4 and 16 mg/kg doses, respectively. Zopiclone, when administered to monkeys at a dose of 16 mg/kg/day for 28 days, precipitated withdrawal signs of moderate severity. Peak symptoms appeared three and four days after withdrawal and included hyperirritability, restlessness, tremor, and some weight loss. The administration of a higher dose for two weeks brought about similar symptoms upon withdrawal without precipitating convulsions. Zopiclone was self-administered both intravenously and intragastrically in monkeys. When the drug was changed to saline, the rate of self-administration declined rapidly. 4. Cardiovascular and Respiratory Effects Zopiclone was evaluated in conscious and anesthetized cats, dogs, rabbits and monkeys with regard to its effect on respiration and several cardiovascular parameters. Most of the studies involved i.v. administration. In general, respiration and blood pressure decreased in a dose-dependent fashion while heart rate and EKG showed little change. Zopiclone affected central respiratory control mechanisms to a greater extent than the cardiovascular regulatory mechanisms. 5. Drug-Interaction Studies Zopiclone was evaluated in combination with several drugs and in general interacted either in an additive or synergistic fashion with diazepam,phenobarbital, trimethadione, chlorpromazine, hexobarbital, and ethanol. Zopiclone did not modify the effects of phenytoin, morphine, ketoprofen and gallamine. The effects of zopiclone could be reversed by Ro (flumazenil) a specific benzodiazepine antagonist. ACT ZOPICLONE Page 24 of 40

25 TOXICOLOGY Acute Toxicity Studies were carried out in both sexes of several species. The results are summarized in the Table. SPECIES ROUTE LD 50 (mg/kg) Mice i.v. i.p. p.o Rats p.o Dogs p.o. i.v. > 4500 ~ 400 Cats p.o. > 1500 Rabbits p.o. ~ 2500 Monkeys p.o. > 4500 Symptoms of toxicity included sedation, CNS depression, ataxia, respiratory depression, and dyspnea. In dogs, the i.v. administration of zopiclone was followed by myoclonic seizures. Long Term Toxicity Studies 1. Rats (CD Strain) One-month oral study Ten rats/sex/dose received zopiclone by gavage six days per week at doses of 0, 6, 24, and 120 mg/kg. Dose-related sedation and paresis of hind legs were observed. Thyroid weights were increased in male rats at all dose levels. In the high dose males, heart and spleen weights were reduced. Three-month oral study Fifteen rats/sex/dose received zopiclone by gavage seven days per week at doses of 0, 2, 12 and 120 mg/kg. At the mid and high doses, dose-related hypotonia, adynamia and ptosis were observed, all of which subsided with time. Weight gain was slightly but significantly less in mid and high dose male rats than in controls. At the 120 mg/kg dose the following changes occurred. BSP values decreased in both sexes; the number of RBC decreased in females; liver weights increased in both males and females, accompanied by slight changes in the parenchymal liver cells, namely eosinophilia or basophilia in the portal area. ACT ZOPICLONE Page 25 of 40